The goal of this research is to further our understanding of the interactions of a novel cytokine, prolactin-like protein- A (PLP-A ) and Natural Killer cells. PLP-A is synthesized and secreted by trophoblast cells of the developing chorioallantoic placenta and is targeted toward Natural Killer cells located within the uteroplacental compartment. Natural Killer cells are a part of the immune surveillance, are cytolytically active toward various cell populations, and express an assortment of cytokines. During gestation, Natural Killer cells exhibit temporal- and spatial-specific patterns of appearance within the uteroplacental compartment proximal to the developing chorioallantoic placenta. Phenotypically, the spectrum of uterine Natural Killer cell activities undergoes a gestational-dependent transformation. By midpregnancy, uterine Natural Killer cells show minimal cytolytic activities and express a unique array of secretory products. These adjustments in Natural Killer cell function facilitate the establishment and maintenance of pregnancy. We have shown that the trophoblast cell-specific product, PLP-A, directs gestational-dependent changes in the behavior of uterine Natural Killer cells and in doing so facilitates the establishment and maintenance of pregnancy. In this research project, we propose to identify and characterize PLP-A receptors responsible for initiating PLP-A's effects of natural Killer cells. The planned research utilizes cellular and molecular and in vitro and in vivo strategies. Data derived from the proposed experimentation will improve our understanding of the nature of trophoblast-Natural Killer cell signaling and the role of uterine Natural Killer cells in the establishment and maintenance of the gestational state. These findings will provide considerable insight into the etiology of developmental disorders associated with pregnancy failure and will also have important ramifications on our understanding of the control of Natural Killer cell functions in aberrant processes such as immune disease and cancer.